Isosorbide Mononitrate

Pharmaceuticals -> Metabolite of Isosorbide Dinitrate

Pharmaceuticals -> Listed in ZINC15

-0.9

-0.15

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Isosorbide-5-mononitrate is a crystalline solid. It is very flammable and may be toxic by ingestion.

Solid

Danger

H228 (95.7%): Flammable solid [Danger Flammable solids]

P203, P210, P240, P241, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P370+P378, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 93 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H228: Flammable solid [Danger Flammable solids]

Excerpt from ERG Guide 133 [Flammable Solids]:

· Flammable/combustible material.

Excerpt from ERG Guide 133 [Flammable Solids]:

· Fire may produce irritating and/or toxic gases.

Isosorbide-5-mononitrate

UN3251

Div 4.1 Flammable solid (49 eCFR § 173.124)

PG III: the degree of danger presented by the material is minor

Flam. Sol. 1 (95.7%)

Flammable solids - Category 2

· CALL 911. Then call emergency response telephone number on shipping paper. If shipping paper not available or no answer, refer to appropriate telephone number listed on the inside back cover.

· ELIMINATE all ignition sources (no smoking, flares, sparks or flames) from immediate area.

Excerpt from ERG Guide 133 [Flammable Solids]:

General First Aid:

Excerpt from ERG Guide 133 [Flammable Solids]:

Immediate precautionary measure

Drug Induced Liver Injury Rank (DILIrank 2.0)

Isosorbide mononitrate

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

C - Cardiovascular system

QC - Cardiovascular system

Isosorbide mononitrate is an anti-anginal agent and vasodilator that relaxes vascular smooth muscle to prevent and manage angina pectoris. The pharmacological action is mediated by the active metabolite, [nitric oxide], which is released when isosorbide mononitrate is metabolized. Nitric oxide works on both arteries and veins, but predominantly veins: by relaxing veins and reducing the central venous pressure, nitric oxide causes venous pooling and a decrease in the venous return to the heart, thus decreasing cardiac preload. In healthy subjects, the stroke volume is decreased and venous pooling can occur in the standing posture, leading to postural hypotension and dizziness. At therapeutic doses of isosorbide mononitrate, nitric oxide has a bigger effect on larger muscular arteries over small resistance arteries. Arterial relaxation leads to reduced systemic vascular resistance and systolic blood (aortic) pressure, decreasing to decreased cardiac afterload. The direct dilator effect on coronary arteries opposes the coronary artery spasm in variant angina or angina pectoris. At larger doses, nitric oxide causes the resistance arteries and arterioles to dilate, reducing arterial pressure via coronary vasodilatation. This leads to increased coronary blood flow. Reduced cardiac preload and afterload caused by nitric oxide causes a reduction in myocardial oxygen consumption; decreased myocardial oxygen demand, along with increased coronary blood flow, leads to an increased in the oxygen content of coronary sinus blood and the relief from ischemia. The end effect of isosorbide mononitrate include decreased cardiac oxygen consumption, redistribution coronary flow toward ischemic areas via collaterals, and the relief of coronary spasms. Nitric oxide can also increase the rate of relaxation of cardiac muscles, which is an effect outside of vascular smooth muscles. Organic nitrates can also relax other types of smooth muscles, including esophageal and biliary smooth muscle. The anti-anginal activity of isosorbide mononitrate was observed about 1 hour after dosing, and the peak effect was achieved from 1-4 hours after dosing. The duration of anti-anginal action of at least 12 hours was observed with an asymmetrical dosing regimen.

Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activates the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP₃-mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells.

LX1OH63030

ISOSORBIDE MONONITRATE

Established Pharmacologic Class [EPC] - Nitrate Vasodilator

Chemical Structure [CS] - Nitrates

Physiologic Effects [PE] - Vasodilation

Isosorbide mononitrate is a Nitrate Vasodilator. The physiologic effect of isosorbide mononitrate is by means of Vasodilation.

Drugs used to cause dilation of the blood vessels.

A diverse group of agents, with unique chemical structures and biochemical requirements, which generate NITRIC OXIDE. These compounds have been used in the treatment of cardiovascular diseases and the management of acute myocardial infarction, acute and chronic congestive heart failure, and surgical control of blood pressure. (Adv Pharmacol 1995;34:361-81)

Upon oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has a dose-linear kinetics and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration.

In a human radio-labelled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours. Among the excreted dose, nearly half of the dose was found de-nitrated in urine as isosorbide and sorbitol: approximately 30% is excreted as isosorbide and about 17% is the 2-glucuronide of mononitrate. These metabolites were not vasoactive or pharmacologically active. Renal excretion was complete after 5 days, and fecal excretion accounted for only 1% of drug elimination.

The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water.

The total body clearance is 115-120 mL/min.